Sphingosine 1-Phosphate, a Bioactive Sphingolipid Abundantly Stored in Platelets, Is a Normal Constituent of Human Plasma and Serum

Abstract

Although sphingosine 1-phosphate (Sph-1-P) is reportedly involved in diverse cellular processes and the physiological roles of this bioactive sphingolipid have been strongly suggested, few studies have revealed the presence of Sph-1-P in human samples, including body fluids and cells, under physiological conditions. In this study, we identified Sph-1-P as a normal constituent of human plasma and serum. The Sph-1-P levels in plasma and serum were 191+/-79 and 484+/-82 pmol/ml (mean+/-SD, n=8), respectively. Furthermore, when Sph-1-P was measured in paired plasma and serum samples obtained from 6 healthy adults, the serum Sph-1-P/plasma Sph-1-P ratio was found to be 2.65+/-1.26 (mean+/-SD). It is most likely that the source of discharged Sph-1-P during blood clotting is platelets, because platelets abundantly store Sph-1-P compared with other blood cells, and release part of their stored Sph-1-P extracellularly upon stimulation. We also studied Sph-1-P-related metabolism in plasma. [3H]Sph was stable and not metabolized at all in plasma, but was rapidly incorporated into platelets and metabolized mainly to Sph-1-P in platelet-rich plasma. [3H]Sph-1-P was found to be unchanged in plasma, revealing that plasma does not contain the enzymes needed for Sph-1-P degradation. In summary, platelets can convert Sph into Sph-1-P, and are storage sites for the latter in the blood. In view of the diverse biological effects of Sph-1-P, the release of Sph-1-P from activated platelets may be involved in a variety of physiological and pathophysiological processes, including thrombosis, hemostasis, atherosclerosis and wound healing.

Inhibitory Regulation of Rac Activation, Membrane Ruffling, and Cell Migration by the G Protein-Coupled Sphingosine-1-Phosphate Receptor EDG5 but Not EDG1 or EDG3

“…S1P is unique and distinct from these chemorepellants in that it bidirectionally regulates cell migration, i.e., S1P acts as a chemoattractant for certain cell types (34,40,41,73), while it strongly inhibits cell migration in others (12,31,59,72,77); the latter include several tumorderived cell types. S1P is a normal constituent of the blood and is present at a substantially high concentration (Ͼ0.1 M), most of which is bound to albumin (79). This suggests that blood-borne mediator S1P is capable of regulating cell motility in various tissues.…”

Sphingosine 1-Phosphate Stimulates Insulin Secretion in HIT-T 15 Cells and Mouse Islets.

“…S1P also increases insulin secretion from isolated mouse pancreatic islets, raising the possibility that S 1 P may physiologically be involved in the regulation of non-glucose stimulated insulin secretion in vivo. Although the S 1 P levels in human serum are as low as about 0.5 nM [33], circulating platelets abundantly stores S1P and activated platelets may release S 1 P into the extracellular space in response to physiological agonists such as thrombin [34], resulting in a marked increase of local S1P concentrations.…”

Sphingosine-1-phosphate receptor 2 protects against anaphylactic shock through suppression of endothelial nitric oxide synthase in mice

“…3 Plasma S1P, which is present at the concentration of ~10 -6 M, is derived from erythrocytes, vascular endothelial cells (EC) and other cells. [4][5][6] Most of the biological activities of S1P are mediated by the S1P-specific G protein-coupled receptor family S1P 1~ S1P 5 . 7 Among these, S1P 1 , S1P 2 and S1P 3 are widely expressed major receptor subtypes.…”